To date, more than 100 genes have been mapped or cloned that may be associated with retinal degeneration. The pathogenesis of retinal degenerative diseases such as age-related macular degeneration (ARMD) and retinitis pigmentosa (RP) is multifaceted and can be triggered by environmental factors in those who are genetically predisposed. One such environmental factor, light exposure, has been identified as a contributing factor to the progression of retinal degenerative disorders such as ARMD (Young, Survey of Opthalmology, 1988, Vol. 32:252-269). Photo-oxidative stress leading to light damage to retinal cells has been shown to be a useful model for studying retinal degenerative diseases for the following reasons: damage is primarily to the photoreceptors and retinal pigment epithelium (RPE) of the outer retina (Noell, et al., Investigative Opthalmology & Visual Science, 1966, Vol. 5:450-472; Bressler, et al., Survey of Opthalmology, 1988, Vol. 32:375-413; Curcio, et al., Investigative Opthalmology & Visual Science, 1996, Vol. 37:1236-1249); they share a common mechanism of cell death, apoptosis (Ge-Zhi, et al., Transactions of the American Opthalmology Society, 1996, Vol. 94:411-430; Abler, et al., Research Communications in Molecular Pathology and Pharmacology, 1996, Vol. 92:177-189); light has been implicated as an environmental risk factor for progression of ARMD and RP (Taylor, et al., Archives of Opthalmology, 1992, Vol. 110:99-104; Naash, et al., Investigative Opthalmology & Visual Science, 1996, Vol. 37:775-782); and therapeutic interventions which inhibit photo-oxidative injury have also been shown to be effective in animal models of heredodegenerative retinal disease (LaVail, et al., Proceedings of the National Academy of Science, 1992, Vol. 89:11249-11253; Fakforovich, et al., Nature, 1990, Vol. 347:83-86).
A number of different classes of compounds have been reported to minimize retinal photic injury in various animal models, including: antioxidants, such as, ascorbate (Organisciak, et al., Investigative Opthalmology & Visual Science, 1985, Vol. 26:1580-1588), dimethylthiourea (Organisciak, et al., Investigative Opthalmology & Visual Science, 1992, Vol. 33:1599-1609; Lam, et al., Archives of Opthalmology, 1990, Vol. 108:1751-1757), α-tocopherol (Kozaki, et al., Nippon Ganka Gakkai Zasshi, 1994, Vol. 98:948-954), and β-carotene (Rapp, et al., Current Eye Research, 1996, Vol. 15:219-223); calcium antagonists, such as, flunarizine, (Li, et al., Experimental Eye Research, 1993, Vol. 56:71-78; Edward, et al., Archives of Opthalmology, 1992, Vol. 109:554-622); growth factors, such as, basic-fibroblast growth factor (bFGF), brain-derived nerve factor (BDNF), ciliary neurotrophic factor (CNTF), and interleukin-1-β (LaVail, et al., Proceedings of the National Academy of Science, 1992, Vol. 89: 11249-11253); glucocorticoids, such as, methylprednisolone (Lam, et al., Graefes Archives of Clinical & Experimental Opthalmology, 1993, Vol. 231:729-736), dexamethasone (Fu, J., et al., Experimental Eye Research, 1992, Vol. 54:583-594); NMDA-antagonists, such as, eliprodil and MK-801 (Collier, et al., Investigative Opthalmology & Visual Science, 1999, Vol. 40, pg. 5159) and iron chelators, such as, desferrioxamine (Li, et al., Current Eye Research, 1991, Vol. 2:133-144).
Ophthalmic β-adrenergic antagonists, also referred to as β-adrenoceptor antagonists or β-blockers are well documented IOP-lowering agents for therapy of glaucoma. Currently, several ophthalmic β-blockers are approved for use worldwide. The majority of these are nonselective β-blockers; betaxolol is a cardioselective β-blocker marketed as Betoptic® or Betoptic®S (Alcon Laboratories, Inc., Fort Worth, Tex.).
As a potential treatment for glaucoma and other inner retina pathologies, Osborne, et al. (Brain Research, 1997, Vol. 751:113-123) have shown that betaxolol is neuroprotective in a rat ischemia/reperfusion injury model. Ischemia/reperfusion results in a reduction of the electroretinogram (ERG) b-wave amplitude, a measure of inner retina function, not photoreceptor or RPE function. This ERG b-wave deficit was protected by treatment with betaxolol. Consistent with the inner retinal protection was preservation of choline acetyltransferase and calretinin immunoreactivity in the inner plexiform layer and cell bodies in the ganglion cell layer and inner nuclear layer by treatment with betaxolol. In vitro studies by Osborne, et al. have also shown that betaxolol can prevent the kainate induced elevation of intracellular calcium in chick retinal cells, partially inhibited changes in GABA immunoreactivity in the rabbit inner retina following glucose-oxygen deprivation, and partially prevented the glutamate-induced release of lactate dehydrogenase in cortical cultures. β-adrenoceptor antagonists have also been shown to relax KC1-induced contraction of porcine ciliary artery (Hester, et al., Survey of Opthalmology, Vol. 38:S125-S134, 1994). Moreover, certain β-blockers have been shown to produce vasorelaxation unrelated to their β-adrenergic blocking action (Yu, et al., Vascular Risk Factors and Neuroprotection in Glaucoma, pp. 123-134, (Drance, S. ed.) Update, 1996; Hoste, et al., Current Eye Research, Vol. 13:483-487, 1994; and Bessho, et al., Japanese Journal of Pharmacology, Vol. 55:351-358, 1991.) There is experimental evidence that this is due to the ability of certain β-blockers to act as calcium channel blockers and to reduce the entry of calcium ion into vascular smooth muscle cells to where it participates in the contraction response and reduces the diameter of the lumen of the blood vessel and decreases blood flow.